bi-201335 and Hepatitis-C

Hepatitis C virus (HCV) mortality and morbidity is a world health misery with an approximate 130-150 million chronically HCV tainted and suffering individuals and it initiate critical liver malfunction like cirrhosis, hepatocellular carcinoma or liver HCV cancer. HCV NS5B protein one of the best studied therapeutic target for the identification of new drug candidates to be added to the combination or multiple combination medication recently approved. During the past few years, NS5B has thus been an important object of attractive medicinal chemistry endeavors, which induced to the surfacing of betrothal preclinical drug molecules. In this scenario, the current review set limit to discuss research published on NS5B and few other therapeutic functional inhibitors concentrating on hit investigation, hit to lead optimization, ADME parameters evaluation, and the SAR data which was out for each compound type and similarity taken into consideration. The discussion outlined in this specific review will surly helpful and vital tool for those medicinal chemists investigators working with HCV research programs mainly pointing on NS5B and set broad spectrum identification of creative anti HCV compounds. This mini review also tells each and every individual compound ability related how much they are active against NS5B and few other targets.

Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Humans; Polyproteins; Structure-Activity Relationship; Viral Nonstructural Proteins

Historically, pegylated interferon in combination with ribavirin was the standard of care in hepatitis C virus; however, this combination is often poorly tolerated, has a significant side-effect profile and is of limited efficacy in hepatitis C virus genotype-1. More recently, pegylated interferon/ribavirin has been combined with direct acting antiviral agents such as the first generation NS3/4A protease inhibitors. Faldaprevir, a first generation, second-wave protease inhibitor, when used with a pegylated interferon/ribavirin regimen, has also been shown to increase treatmentsuccess while shortening treatment duration; however, second generation direct acting antiviral agents offer even betterefficacy and tolerability. Various direct acting antiviral agent combinations in interferon-free regimens have been effective in over 95% of patients and are now in licensed use. While faldaprevir was a pioneering drug, by the time it reached late phase development it was superseded by newer agents.

Topics: Aminoisobutyric Acids; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Interferons; Leucine; Oligopeptides; Polyethylene Glycols; Proline; Protease Inhibitors; Quinolines; Ribavirin; Thiazoles

The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved the HCV NS3/4A protease inhibitor simeprevir and the HCV NS5B polymerase inhibitor sofosbuvir. Simeprevir or sofosbuvir in combination with pegylated interferon and ribavirin are available for clinical use. Faldaprevir, another HCV NS3/4A protease inhibitor that also has fewer adverse events than telaprevir or boceprevir, is under development. Of interest, faldaprevir in combination with pegylated interferon and ribavirin, and interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provides high sustained virological response rates for HCV genotype 1 infection. The aim of this article is to review these data concerning faldaprevir. Faldaprevir in combination with pegylated interferon and ribavirin treatment appears to be associated with fewer adverse events than telaprevir or boceprevir in combination with pegylated interferon and ribavirin, and may be one of the therapeutic options for treatment-naive patients with HCV genotype 1. The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection and may hold promise for interferon-ineligible and interferon-intolerant patients.

Topics: Aminoisobutyric Acids; Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Leucine; Oligopeptides; Polyethylene Glycols; Proline; Quinolines; Thiazoles; Viral Nonstructural Proteins

Enormous progress has been made in the understanding of the hepatitis C virus and the development of novel therapeutic agents since the identification of the virus, from initial interferon monotherapy to PEGylated interferon in combination with ribavirin for 48-72 weeks that used to be the standard of care in hepatitis C virus therapy. However, this combination has limited efficacy and a significant side effect profile including flu-like symptoms, anemia, leukopenia, autoimmune disorders and depression, so it is often poorly tolerated. Recently, direct-acting antiviral agents, such as the first-generation NS3/4A protease inhibitors, have been added to this combination, improving the percentage of successful treatments. Faldaprevir is a first-generation, second wave, protease inhibitor that, when combined with PEGylated interferon and ribavirin, has been shown to increase treatment success with shorter treatment duration. Various direct-acting antiviral agent combinations in interferon-free regimens have been effective in over 95% of patients and are now in licensed use.

Topics: Aminoisobutyric Acids; Animals; Antiviral Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Discovery; Drug Interactions; Hepatitis C; Humans; Leucine; Molecular Structure; Oligopeptides; Proline; Quinolines; Thiazoles; Tissue Distribution; Treatment Outcome; Viral Nonstructural Proteins

Hepatitis C virus (HCV)-related liver disease is a major source of mortality in HIV-infected patients. Approximately one third of all patients with HIV are co-infected with HCV. Patients co-infected with HIV/HCV have shown lower rates of sustained virologic response with pegylated-interferon and weight-based ribavirin as well as more rapid progression of fibrosis than those with HCV mono-infection. Several direct-acting antiviral agents (DAAs), developed originally for HCV mono-infection, are being reevaluated for HIV/HCV co-infection. In addition, entirely new DAAs are being developed, including, interferon-free regimens with fewer side effects, allowing novel treatment opportunities for difficult-to-treat patients. In order for HCV DAAs to be successfully used in the HIV/HCV co-infected population several hurdles must be overcome, including adverse event management and drug-drug interactions. The aim of this review is to discuss the results of trials for new HCV therapies being developed for HIV/HCV co-infected patients and the impact of interferon-free regimens on treatment in the future.

Topics: Aminoisobutyric Acids; Antiviral Agents; Coinfection; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Interferons; Leucine; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Viral Nonstructural Proteins

In recent years, several studies have clearly shown that sustained virological response (SVR) achieved by interferon-based therapies may delay or reduce the risk of hepatocellular carcinoma, liver decompensation and all-causes of mortality in all categories of patients with HCV-related cirrhosis, a condition characterized by a wide heterogeneity of clinical features, especially in patients with compensated disease. Unfortunately, the advanced fibrosis stage has been shown to be associated with poor SVR rates and poor tolerance with Peg-interferon and ribavirin. Therefore, on the basis of its risk/efficacy evaluation, most patients are considered to be ineligible for antiviral therapy with these molecules. Recently, improvement in the knowledge of the HCV life-cycle, has resulted in the rapid development of many direct-acting antivirals (DAAs). Two first generation DAAs, boceprevir (BOC) and telaprevir (TVR), have been approved, and more than 40 new small molecules are still in development. However, only a few individuals with compensated cirrhosis were included in the phase III studies assessing the safety and efficacy of BOC or TVR in naïve and chronic hepatitis C genotype 1 patients in whom treatment had failed, and patients with either decompensation or end-stage liver disease were excluded. Therefore, the information available in these patients, which have shown significantly lower SVR compared with patients with mild to moderate fibrosis, are not fully reliable. In addition, in real practice, some studies that have not yet been fully published have shown that triple therapy with these two molecules was associated with low SVR and high serious adverse events (SAEs).

Topics: Algorithms; Aminoisobutyric Acids; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Leucine; Liver Cirrhosis; Oligopeptides; Proline; Quinolines; Simeprevir; Sofosbuvir; Sulfonamides; Thiazoles; Time Factors; Uridine Monophosphate

Treating hepatitis C virus (HCV) in HIV/HCV co-infected patients is a challenge. Even if the benefits of achieving a sustained virological response are clear, the rates achieved with the combination of pegylated-interferon and ribavirin are disappointing. The addition of direct acting antiviral agents (DAAs) to the treatment of hepatitis C is revolutionizing the treatment of HCV in mono-infected patients. Even if there have not been any agents approved for the treatment of co-infected patients, many studies specifically designed for this population are ongoing. This article reviews available data on the use of DAAs in co-infected patients and the challenges associated with these new drugs.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Coinfection; Drug Interactions; Drug Therapy, Combination; Hepacivirus; Hepatitis C; HIV Infections; Humans; Imidazoles; Leucine; Oligopeptides; Proline; Pyrrolidines; Quinolines; Sofosbuvir; Thiazoles; Treatment Outcome; Uridine Monophosphate; Valine

With the approval of second-wave direct-acting antivirals simeprevir, sofosbuvir and faldaprevir in 2014-2015, for genotype 1 hepatitis C, patients and doctors will have more treatment options. During a first period, these treatments will still be used with peginterferon and ribavirin. The second wave of IFN-based triple therapy will have benefits and risk. These treatments have the following advantages: higher efficacy with more patient candidates for a shorten treatment duration (12-24 weeks, instead of 48 weeks). These new treatments appear to have a better safety profile than first generation, with no additional increase in anaemia over peginterferon/ribavirin. Then, these treatments are to take for patients with a decrease in pill burden (these three direct-acting antivirals are given orally one pill a day). Simeprevir and sofosbuvir may be approved in the US and Europe, in 2014, at the time this manuscript will be released. Approval of faldaprevir will follow. These direct-acting antivirals with many others will hopefully be combined in future interferon-free regimens. The goal of this review to summarize the results and safety of simeprevir, faldaprevir and sofosbuvir, to advise physicians and to inform patients on the benefits and risks of these second-wave IFN-based regimens for HCV genotype infection.

Topics: Aminoisobutyric Acids; Antiviral Agents; Clinical Trials as Topic; Drug Approval; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Leucine; Oligopeptides; Proline; Quinolines; Simeprevir; Sofosbuvir; Sulfonamides; Thiazoles; Time Factors; Uridine Monophosphate

For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct-acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan-genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN-based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross-resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Clinical Trials as Topic; Disease Eradication; Drug Discovery; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Interferon-alpha; Isoquinolines; Leucine; Oligopeptides; Polyethylene Glycols; Proline; Protease Inhibitors; Pyrrolidines; Quinolines; Recombinant Proteins; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Thiazoles; Uridine Monophosphate; Valine; Viral Nonstructural Proteins; Virus Replication

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease and a leading indication of liver transplantations worldwide. The current standard of care for chronic hepatitis C is a combination of pegylated interferon-α and ribavirin that is effective in slightly more than half of cases and is associated with significant side effects. The first directly acting antivirals recently reached the US market, but will have shortcomings that should in part be overcome by the second-wave PIs that are in development. This article gives an overview of the compounds that will soon be available.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carrier Proteins; Cyclopropanes; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Intracellular Signaling Peptides and Proteins; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Viral Nonstructural Proteins

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single-centre, open-label, fixed-sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co-administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co-administered with FDV was similar to CsA alone. However, the AUC

Topics: Adolescent; Adult; Aminoisobutyric Acids; Antiviral Agents; Area Under Curve; Cross-Over Studies; Cyclosporine; Drug Interactions; Female; Graft Rejection; Healthy Volunteers; Hepatitis C; Humans; Immunosuppressive Agents; Leucine; Liver Transplantation; Male; Middle Aged; Oligopeptides; Proline; Prospective Studies; Quinolines; Secondary Prevention; Tacrolimus; Thiazoles; Young Adult

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).

Topics: Adult; Aged; Aminoisobutyric Acids; Biological Availability; Female; Half-Life; Hepatitis C; Humans; Leucine; Male; Middle Aged; Oligopeptides; Proline; Quinolines; Renal Insufficiency; Thiazoles

The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms.

Topics: Adolescent; Adult; Aminoisobutyric Acids; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Hepatitis C; Humans; In Vitro Techniques; Isoenzymes; Leucine; Male; Microsomes, Liver; Midazolam; Middle Aged; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Thiazoles; Warfarin; Young Adult

Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin.. HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression.. In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12.. The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes.. ClinicalTrials.gov: NCT01132313.

Topics: Acrylates; Aminoisobutyric Acids; Anemia; Antiviral Agents; Benzimidazoles; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Interferons; Leucine; Male; Middle Aged; Oligopeptides; Polymorphism, Single Nucleotide; Proline; Pyrophosphatases; Quinolines; Real-Time Polymerase Chain Reaction; Ribavirin; Thiazoles

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).

Topics: Adolescent; Adult; Aged; Aminoisobutyric Acids; Antiviral Agents; Carrier Proteins; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Intracellular Signaling Peptides and Proteins; Leucine; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Quinolines; Recombinant Proteins; Ribavirin; RNA, Viral; Thiazoles; Viral Nonstructural Proteins; Young Adult

Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients.. In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination. To assess potential drug interactions, geometric mean ratios and 90% confidence intervals for PK parameters were calculated. Safety was evaluated.. Efavirenz decreased faldaprevir area under the concentration-time curve (AUC) by 35%, Cmax by 28%, and Cmin by 46%, consistent with induction of CYP3A by efavirenz. Tenofovir decreased faldaprevir AUC by 22%, which was not considered to be clinically relevant. Faldaprevir had no clinically relevant effects on darunavir or tenofovir PK (15% and 22% AUC increase, respectively). Adverse events were consistent with the known safety profiles of faldaprevir and the antiretrovirals being examined.. No clinically significant interactions were observed between faldaprevir and darunavir/ritonavir or tenofovir. A potentially clinically relevant decrease in faldaprevir exposure was observed when coadministered with efavirenz; this decrease can be managed using the higher of the 2 faldaprevir doses tested in phase 3 trials (240 mg once daily as opposed to 120 mg once daily).

Topics: Adenine; Adult; Alkynes; Aminoisobutyric Acids; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Coinfection; Cyclopropanes; Darunavir; Drug Interactions; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Leucine; Male; Middle Aged; Oligopeptides; Organophosphonates; Proline; Protease Inhibitors; Quinolines; Ritonavir; Sulfonamides; Tenofovir; Thiazoles; Young Adult

Faldaprevir, an investigational agent for hepatitis C virus treatment, is well tolerated but associated with rapidly reversible, dose-dependent, clinically benign, unconjugated hyperbilirubinemia. Multidisciplinary preclinical and clinical studies were used to characterize mechanisms underlying this hyperbilirubinemia. In vitro, faldaprevir inhibited key processes involved in bilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC50 0.45 µM), which conjugates bilirubin, and hepatic uptake and efflux transporters, organic anion-transporting polypeptide (OATP) 1B1 (IC50 0.57 µM), OATP1B3 (IC50 0.18 µM), and multidrug resistance-associated protein (MRP) 2 (IC50 6.2 µM), which transport bilirubin and its conjugates. In rat and human hepatocytes, uptake and biliary excretion of [(3)H]bilirubin and/or its glucuronides decreased on coincubation with faldaprevir. In monkeys, faldaprevir (≥20 mg/kg per day) caused reversible unconjugated hyperbilirubinemia, without hemolysis or hepatotoxicity. In clinical studies, faldaprevir-mediated hyperbilirubinemia was predominantly unconjugated, and levels of unconjugated bilirubin correlated with the UGT1A1*28 genotype. The reversible and dose-dependent nature of the clinical hyperbilirubinemia was consistent with competitive inhibition of bilirubin clearance by faldaprevir, and was not associated with liver toxicity or other adverse events. Overall, the reversible, unconjugated hyperbilirubinemia associated with faldaprevir may predominantly result from inhibition of bilirubin conjugation by UGT1A1, with inhibition of hepatic uptake of bilirubin also potentially playing a role. Since OATP1B1/1B3 are known to be involved in hepatic uptake of circulating bilirubin glucuronides, inhibition of OATP1B1/1B3 and MRP2 may underlie isolated increases in conjugated bilirubin. As such, faldaprevir-mediated hyperbilirubinemia is not associated with any liver injury or toxicity, and is considered to result from decreased bilirubin elimination due to a drug-bilirubin interaction.

Topics: Aminoisobutyric Acids; Animals; Bilirubin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Double-Blind Method; Glucuronosyltransferase; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Hyperbilirubinemia; Leucine; Liver; Macaca mulatta; Multicenter Studies as Topic; Multidrug Resistance-Associated Protein 2; Oligopeptides; Proline; Quinolines; Randomized Controlled Trials as Topic; Rats; Thiazoles

BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.. Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.. In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL<25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.. BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.

Topics: Adult; Aminoisobutyric Acids; Antiviral Agents; Carrier Proteins; Double-Blind Method; Drug Resistance, Viral; Female; Hepacivirus; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Intracellular Signaling Peptides and Proteins; Leucine; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Protease Inhibitors; Quinolines; Recombinant Proteins; Ribavirin; Thiazoles; Viral Load; Viral Nonstructural Proteins

Several combinations of 2 or 3 direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naive patients. DAAs for HCV infection have similar mechanisms of action and chemical structures to antiretrovirals for human immunodeficiency virus (HIV) infection. Generic antiretrovirals are currently manufactured at very low prices, to treat 10 million people with HIV/AIDS in developing countries.. Four HCV DAAs, currently either in phase 3 development or recent approval (daclatasvir, sofosbuvir, simeprevir, faldaprevir), and ribavirin were classified by chemical structure, molecular weight, total daily dose, and complexity of synthesis. The likely range of manufacturing costs per gram of DAA were then projected as formulated product cost, based upon treating a minimum of 1 million patients annually (to arrive at volume demand) combined with an analysis of the complexity of synthesis and a 40% margin for formulation. Projections were then compared with actual costs of antiretrovirals with similar structures.. Minimum manufacturing costs of antiretrovirals were US$0.2-$2.1 per gram. The complexity of chemical synthesis for HCV DAAs was ranked from lowest to highest: ribavirin, daclatasvir, sofosbuvir, faldaprevir, and simeprevir. Predicted manufacturing costs (US dollars) for 12-week courses of HCV DAAs were $21-$63 for ribavirin, $10-$30 for daclatasvir, $68-$136 for sofosbuvir, $100-$210 for faldaprevir, and $130-$270 for simeprevir.. Within the next 15 years, large-scale manufacture of 2 or 3 drug combinations of HCV DAAs is feasible, with minimum target prices of $100-$250 per 12-week treatment course. These low prices could make widespread access to HCV treatment in low- and middle-income countries a realistic goal.

Topics: Aminoisobutyric Acids; Anti-HIV Agents; Antiviral Agents; Carbamates; Developing Countries; Drug Industry; Drug Therapy, Combination; Health Services Accessibility; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Leucine; Oligopeptides; Proline; Pyrrolidines; Quinolines; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Thiazoles; Uridine Monophosphate; Valine

Hepatitis C virus infection, a major cause of liver disease worldwide, is curable, but currently approved therapies have suboptimal efficacy. Supplementing these therapies with direct-acting antiviral agents has the potential to considerably improve treatment prospects for hepatitis C virus-infected patients. The critical role played by the viral NS3 protease makes it an attractive target, and despite its shallow, solvent-exposed active site, several potent NS3 protease inhibitors are currently in the clinic. BI 201335, which is progressing through Phase IIb trials, contains a unique C-terminal carboxylic acid that binds noncovalently to the active site and a bromo-quinoline substitution on its proline residue that provides significant potency. In this work we have used stopped flow kinetics, x-ray crystallography, and NMR to characterize these distinctive features. Key findings include: slow association and dissociation rates within a single-step binding mechanism; the critical involvement of water molecules in acid binding; and protein side chain rearrangements, a bromine-oxygen halogen bond, and profound pK(a) changes within the catalytic triad associated with binding of the bromo-quinoline moiety.

Topics: Aminoisobutyric Acids; Carrier Proteins; Catalytic Domain; Clinical Trials, Phase I as Topic; Crystallography, X-Ray; Hepacivirus; Hepatitis C; Humans; Intracellular Signaling Peptides and Proteins; Leucine; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides; Proline; Protease Inhibitors; Protein Binding; Quinolines; Thiazoles; Viral Nonstructural Proteins